The goal of our preclinical studies for cancer treatment are currently focused on preclinical evaluation of combination therapy with two drugs, rapamycin (mTOR inhibitor) and MS-275 (HDAC, histone deactylase inhibitor) which interact with the two signal transduction pathways, RB and PI3K. These drugs have been evaluated in tissue culture cell lines for the following cancers: multiple myeloma, plasmacytoma or plasma cell tumors, and mantle cell lymphoma.Combined treatment with low concentrations of MS-275 and rapamycin resulted in a synergistic effect on growth inhibition in vitro and in vivo. Rapamycin decreased phosphorylation of S6, and MS-275 increased acetylation of histone H3 and H4. Both effects were further accentuated by the combination treatment. Both drugs caused cell cycle arrest, via different signaling events; MS-275 induced the expression of p21, p27 and p16, whereas rapamycin reduced the expression of cyclin D and p21. In contrast to rapamycin alone, the combination treatment did not lead to MAPK or AKT activation. MS-275 and rapamycin increased, and their combination further enhanced, the expression of pro-apoptotic proteins Foxo and Bim, and decreased expression of the pro-survival protein Survivin. The therapeutic potential of the combination was supported by in vivo studies of MM xenografts and PDX model for breast cancer. We were able to document that MYC degradation is significantly enhanced by combining an mTOR inhibitor with an HDAC inhibitor. As a direct result of these studies, we screened small molecule arrays to identify direct inhibitors of MYC.